Insights: UK High Court raises bar for inventive step of dosage regimens whilst clearing the way for marketing of biosimilar Herceptin

In the early 2000s the launch of Trastuzumab, an anti-HER2 antibody with the brand name Herceptin®, heralded the start of a targeted approach to the treatment of cancer. Trastuzumab targets the epidermal receptor HER2, which is overexpressed on the tumour cells of a subset of breast cancer patients, and paved the way for further treatments based upon the markers expressed by a tumour in a particular individual. With the Supplementary Protection Certificate (SPC) for Genentech’s original Trastuzumab patent (EP0590058) due to expire on 28 July 2014, the High Court has now cleared the way for biosimilar Trastuzumab by revoking two of Genentech’s follow on patents in the UK (Hospira UK Limited v Genentech Inc., please click for full decision).

The first patent considered in the decision (EP210115) relates to the intravenous administration of Trastuzumab at an initial dose of 8mg/kg followed by doses of 6mg/kg every three weeks. This differs from the original Trastuzumab dosing schedule which required weekly administration of Trastuzumab in combination with three weekly administration of the mitotic inhibitor Paclitaxel. This patent was revoked by the EPO during opposition proceedings and is currently awaiting appeal at the EPO. In the UK, generics manufacturer Hospira sought to revoke the patent on the basis that the claimed dosage regimen lacks an inventive step and is insufficiently disclosed. The primary piece of prior art cited by Hospira is the FDA label for Herceptin®, which was published upon approval of the product by the FDA.

In considering inventive step the decision indicates that, provided it could be shown to be safe and efficacious, the skilled person would consider using a three weekly Trastuzumab dosage regimen in order to increase patient convenience by coinciding with the paclitaxel dosing. The FDA label illustrates that a 500mg Trastuzumab dose was safe and that at this dose the plasma half-life of Trastuzumab was 12 days. Accordingly, the decision indicates that the skilled person would not dismiss the idea of three weekly dosings, and would instead consult a pharmacokinetics expert in order to determine whether a three weekly Trastuzumab dose would be therapeutically effective. Other prior art publications demonstrated that therapeutically useful serum levels of Herceptin® are maintained three weeks after dosing, and the decision therefore concludes that the prior art would not dissuade a pharmacokinetics expert from advising that a small-scale clinical trial administering Trastuzumab every three weeks should be perfor d. Finally, it was concluded that once the skilled person had decided to perform a clinical trial using three weekly Trastuzumab administrations, the dosage to be given every three weeks would be apparent from the trial results, and cannot be considered inventive.

The decision appears to set a high bar for inventive step of a claim relating to a dosage regimen by requiring that in order to establish inventive step the skilled person must have been so sure that the dosage regimen would not work that they would not have consulted a pharmacokinetics expert. Once it is established that the skilled person would have consulted a pharmacokinetics expert, it will be difficult to establish inventive step of a dosage regimen unless the pharmacokinetics expert would conclude that it was not worthwhile conducting a small-scale clinical trial. From a practical perspective this decision highlights the importance of delaying publications demonstrating the pharmacokinetic properties of a therapeutic agent until it is known whether a dosage regimen patent is required.

Hospira also attacked the patent on the basis that if it was inventive it lacked sufficiency. Although the patent was found to lack inventive step, for completeness sufficiency was briefly considered. Here Mr Justice Birss indicated that the patent would have been found insufficient because the only Example dealing with the claimed dosage regimen (Example 5) is entirely prophetic, and the prior art indicates enough uncertainty to deter the skilled person from performing a clinical trial to establish that the claimed technical effect was plausible. This conclusion suggests that for a dosage regimen to be considered inventive it must not have been obvious to try the claimed dosage regimen. In contrast, a claim to a dosage regimen will be considered insufficiently disclosed, even if it may have been obvious to try, if there is no evidence to suggest that the claimed dosage regimen would be therapeutically effective. This highlights the need to incorporate data into a patent application directed to dosage regimen in order to fulfil the sufficiency requirements.

In the same action the UK High Court revoked EP1308455, relating to a Trastuzumab composition having an improved level of purity, for lack of novelty and issued a declaration of non-infringement to Hospira on the basis that their composition fell outside the scope of the claims. These decisions clear the way for the manufacture of Herceptin® biosimilars once Genentech’s SPC on the original Trastuzumab patent expires in July.